Pyrimidine derivatives as GPCR modulators for use in the treatment of obesity and diabetes

Abstract

The present invention relates to Pyriraidine Derivatives of formula (I), compositions comprising a Pyrimidine Derivative, and methods of using the Pyrimidine Derivatives for treating or preventing obesity, diabetes, a diabetic complication, a metabolic disorder, a cardiovascular disease or a disorder related to the activity of a G protein-coupled receptor (GPCR) in a patient.

What is claimed is: 
     
       1. A compound having the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein:
 R 1  is H, alkyl, halo or —O-alkyl; 
 R 2a  is H or alkyl, or R 2a  and R 2b  join to form —CH 2 CH 2 —, —CH 2 CH 2 CH 2 — or —CH 2 OCH 2 —; 
 R 2b  is H or alkyl; 
 R 3a  is H or alkyl, or R 3a  and R 3b  join to form —CH 2 CH 2 —, —CH 2 CH 2 CH 2 — or —CH 2 OCH 2 —; 
 R 3b  is H or alkyl; 
 R 4  is alkyl, cycloalkyl, haloalkyl, aryl, -alkylene-aryl or heteroaryl, wherein an aryl or heteroaryl group can be optionally substituted with one or more groups, which can be the same or different, and are selected from alkyl, halo, haloalkyl, —O-alkyl, —CN and —S(O) 2 -alkyl; 
 R 5  is alkyl, cycloalkyl, haloalkyl, -alkylene-aryl, alkenyl or —N(alkyl) 2 ; 
 A is a bond; 
 Q is —N—; 
 W is —C(O)—, —C(O)O—, or —S(O) 2 —; 
 Y is —O—, —S—, or —NH—; 
 Z is —CH—; 
 each occurrence of n is independently 0, 1 or 2; and 
 each occurrence of p is 1. 
 
       
     
     
       2. The compound of  claim 1  having the formula: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is H, alkyl, —O-alkyl or halo; 
 R 4  is alkyl, cycloalkyl, haloalkyl, aryl, -alkylene-aryl or heteroaryl, wherein an aryl or heteroaryl group can be optionally substituted with one or more groups, which can be the same or different, and are selected from alkyl, halo, haloalkyl, —O-alkyl, —CN and —S(O) 2 -alkyl; 
 R 5  is alkyl, cycloalkyl, haloalkyl, -alkylene-aryl, alkenyl or —N(alkyl) 2 ; 
 W is —C(O)O—, —C(O)— or —S(O) 2 —; and 
 Y is —O—, —S—, or —NH—; 
 
         or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. 
       
     
     
       3. The compound of  claim 2 , wherein R 1  is methyl, methoxy or F, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. 
     
     
       4. A compound having the structure: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. 
       
     
     
       5. A composition comprising an effective amount of one or more compounds of  claim 1  or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable carrier. 
     
     
       6. A composition comprising an effective amount of one or more compounds of  claim 4  or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable carrier. 
     
     
       7. A method for treating diabetes, obesity or metabolic syndrome in a patient, the method comprising administering to the patient an effective amount of one or more compounds of  claim 1  or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 
     
     
       8. The compound of  claim 1 , wherein each occurrence of n is 1 and each occurrence of p is 1, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. 
     
     
       9. The compound of  claim 1 , wherein R 1  is methyl, methoxy or F, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. 
     
     
       10. The compound of  claim 1 , wherein R 4  is isopropyl, allyl, cyclopropyl, t-butyl, ethyl, pyridyl or phenyl, where a pyridyl or phenyl group can be optionally substituted with one or more groups, which can be the same or different, and which are selected from halo and haloalkyl, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. 
     
     
       11. The compound of  claim 1 , wherein R 5  is methyl, isopropyl, cyclopropyl, ethyl, —CH 2 CF 3 , benzyl, —N(CH 3 ) 2  or allyl, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. 
     
     
       12. The compound of  claim 1 , wherein W is —C(O)O—, —C(O)—, or —S(O) 2  and R 4  is alkyl, aryl, heteroaryl, -alkylene-aryl, alkenyl, cycloalkyl or N(alkyl) 2 , or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. 
     
     
       13. The compound of  claim 1 , wherein R 2a , R 2b , R 3a  and R 3b  are each H, or combine to form —CH 2 CH 2 —, —CH 2 CH 2 CH 2 — or —CH 2 OCH 2 —, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. 
     
     
       14. The compound of  claim 2 , wherein R 1  is methyl, methoxy or F, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. 
     
     
       15. The compound of  claim 2 , wherein R 4  is isopropyl, allyl, cyclopropyl, t-butyl, ethyl, pyridyl or phenyl, where a pyridyl or phenyl group can be optionally substituted with one or more groups, which can be the same or different, and which are selected from halo and haloalkyl, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. 
     
     
       16. The compound of  claim 2 , wherein R 5  is methyl, isopropyl, cyclopropyl, ethyl, —CH 2 CF 3 , benzyl, —N(CH 3 ) 2  or allyl, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. 
     
     
       17. The compound of  claim 2 , wherein W is —C(O)O—, —C(O)—, or —S(O) 2  and R 4  is alkyl, aryl, heteroaryl, -alkylene-aryl, alkenyl, cycloalkyl or —N(alkyl) 2  and Y is —O, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. 
     
     
       18. The compound of  claim 2 , wherein Y is —O—; R 4  is isopropyl, allyl, cyclopropyl, t-butyl, ethyl, pyridyl or phenyl, where a pyridyl or phenyl group can be optionally substituted with one or more groups, which can be the same or different, and which are selected from halo and haloalkyl; and R 5  is methyl, isopropyl, cyclopropyl, ethyl, —CH 2 CF 3 , benzyl, —N(CH 3 ) 2  or allyl, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. 
     
     
       19. A compound which is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.